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Hereditary sensory autonomic neuropathy Type 1A, or HSAN1A, also named Hereditary Sensory autonomic neuropathy type 1, is a very rare progressive peripheral neuropathy.

Cause

HSAN1A is a genetic disorder.  The cause is a misspelling or a mutation on autosomal dominant SPTLC1 gene.  This gene provides genetic instruction for making the first part of the SPT enzyme, Serine Palmytoyltransferase Long Chain Subunit-1.  SPT enzyme is constituted by three parts, genetic instructions are provided by three genes SPTLC1, SPTLC2, and SPTLC3 respectively.  SPTLC1  is located on chromosome 9, while SPTLC2 is mapped at Chromosome 14, and SPTLC3 is located on chromosome 20^1-5.

It was discovered that a mutation occurring in either SPTLC1 or SPTLC2 could cause HSAN, Hereditary Sensory Autonomic Neuropathy.  A mutation on SPTLC2 causes HSAN1C⁴.  The normal function of SPT enzyme is to catalyze the condensation of the amino acid Serine and Palmitoyl-CoA.  This chemical reaction is the first and rate-limiting step to make sphingolipids that are fundamental components in human cell membranes⁶.

The role of the normal SPT enzyme helps the amino acid L-serine to combine with palmitoyl-CoA and forms a product called sphinganine, or SA.   It is the first step in a series of biochemical chain reactions to make sphingolipids, or SL.  However, the mutated SPT enzyme changes its preferential substrate and incorporate L-alanine, besides L-serine, resulting in a formation of 1-deoxy-sphinganine, or deoxy-SA.  Some mutated SPT enzyme would incorporate not only L-alanine but also L-glycine.  When it incorporates L-glycine, it results in the formation of 1-deoxymethyl-sphinganine, or deoxymethyl-SA.  Both deoxy-SA and deoxymethyl-SA are called deoxysphingolipids, or deoxySL. Researchers discovered that deoxySLs are lacking an important OH group at C₁ of the normal sphinganine in its chemical structure, therefore they are not able to continue to participate in the next steps of the biochemical process to make the sphingolipids nor be degraded through the canonical pathway in the human body.   Instead, they accumulate in the cells and exist in the blood stream⁶.  DeoxySL is found to be toxic to nerves and it builds up to high levels in the sciatic nerve.  It also damages other parts of the peripheral nervous system and affects sensory, motor, and autonomic nerves. Experiments show the sensory neurons are more susceptible to these neurotoxic lipids than the motor neurons.  Autonomic nerves are affected but appear to be less severely^6,13,16.

DeoxySL damages the nerve cell by causing mitochondrial dysfunction; mitochondria are responsible for generating most of chemical energy needed to power the cell’s biochemical reactions.  Low amounts of deoxySL do not cause harm to mitochondria, but as the concentration goes higher, it causes the mitochondria to change their shape, alter their chemical structure, or even fragment.  When the concentration reaches 1 μM, the cell dies⁹.

DeoxySL is also formed in normal and healthy people, but with a very low amount, about 0.1-0.3 μM, which does not affect the cell.  However, HSAN1 patients could go as high as 1.2 μM.  High deoxySL is also found in people who suffer from diabetes type 2 and metabolic syndrome⁹.

Symptoms

HSAN1A primarily affects feet and hands, though for severe cases, it might spread to proximal parts of the body, such as the thighs and upper arms.  It could damage the sensory, motor, and autonomic nerves with the damage on the sensory nerve first and the most.  Affected individuals, at the beginning stage, would experience hyperpathia on their feet for a period of time, then the skin would slowly lose sensation to temperature and to pain.  A while later, loss of sensation would gradually appear on hands as well.  Since feeling no pain, patients often accidentally injure or burn themselves without noticing it^10,11,13.  If the wound is not addressed properly, it is easy to cause repetitive infections and long-term ulcerations that might lead to osteomyelitis and thus risk of amputation.  As the disease progresses, one might suffer tingling, burning, and electric shock-like shooting pain or “lightning pain”on the feet and hands.  Over time these symptoms might move upward to the thigh.   Loss of sensation, in some cases, might happen on the lower abdomen starting from the center line and gradually spreading to the sides and upward to the chest and shoulders.  Feelings of joint position and vibration are affected but much less severely and happen after loss of sensation on the skin¹⁰.

Many patients’ motor functions are also affected, though in variable degrees.  When it happens, one might have muscle weakness and atrophy on the feet and hands.  As a result, patients might experience ankle weakness and difficulty walking on heels or toes.  For severe cases, muscle atrophy might happen on calves or even spread to thigh area^10,11.  When it occurs in the upper limb, one might notice clumsiness with fingers and having difficulty doing detailed work such as picking up tiny objects, buttoning up clothes, or even handwriting.  Usually initial symptoms on upper limbs start to appear a few years after the initial symptoms appear on lower limbs.

Structural foot deformities might occur in HSAN1A patients, such as Charcot feet, high arched feet, flat feet, or hammertoes^10,11.  As time goes by, in the middle or later stages of the disease, more severe cases might need an assistive device in mobility, ie. ankle-support braces, walker, wheelchair or powered wheelchair¹².

Fewer patients experience autonomic nerve impairment.  So far, gastrointestinal symptoms (abdominal pain, constipation, diarrhea, bloating, weight loss)^10,12, heart beat issues, low blood pressure, sweating problems (either sweat too much, too little, or not sweat at all) on hands and feet, and blood vessel (vasomotor) dysfunction have been reported^11,12.  In terms of skin, HSAN1 patients often have delicate skin on the affected areas¹³.  In terms of ophthalmology, pupillary abnormalities (tonic pupil) may happen¹².  Some mutations involve juvenile (at young age) bilateral cataracts^8,15, and a recent study shows that high deoxySL levels links to a specific type of macular disease called Macular telangiectasia type 2¹⁴.

HSAN1A may also cause sensorineural hearing loss.  If it happens, it starts in mid to late adulthood. Intellect is basically not affected.  In terms of life span,  there is a study done on 6 U.K. HSAN1A families which finds that the mean age at death of HSAN1A individuals was 67, slightly earlier than the general U.K. population, probably due to complications of the disease¹⁰.  Moreover, there is a mutation on S331 that affects a very limited number of patients worldwide, with very severe symptoms, and with one patient was unfortunately passed away in his 20’s due to the severity of the illness¹⁵.

Onset time

Initial symptoms are usually seen from second to sixth decade of life¹².  Fewer patients start seeing symptoms in childhood.  The childhood onset cases usually carry and develop more severe symptoms^8,10,15.

The age of onset, symptoms, and severity vary between different individuals of different families and even within the same family¹⁰.  In general, how the disease is revealed in each individual correlates with the type of mutation and the deoxySL level in the patient’s plasma⁹.  Higher deoxySL levels tend to cause more damage to the nerves and increase the severity of the symptoms.  Heavy alcohol use might aggravate the symptoms⁶. It is speculated that other rescue gene(s) or acquired/environmental factors may also play roles in how the symptoms are revealed in different individuals¹⁰. 

C.M.T and HSAN1A

Charcot-Marie-Tooth, or CMT is a group of inherited (genetic) disorders that slowly and progressively damage the peripheral nerves and affect motor and sensory function of lower and upper limbs.  Individuals affected by CMT develop muscle weakness/atrophy and reduced or even lost sensation to temperature and pain on their feet and hands.  So far there are 120+ genes discovered to cause CMT.  Since CMT affects motor and sensory nerves of the peripheral nervous system, it is also named Hereditary motor and sensory neuropathy, or HMSN.  HSAN type 1A,  by its name sounds like the disease only affects sensory and autonomic nerves; however, as symptoms listed above, motor nerves are often affected.  Some HSAN1A patients with sensory and motor nerve impairment with no or minimal autonomic nerve damage would be clinically diagnosed with CMT (or HMSN) ^10,17.  In recent years, SPTLC1 and SPTLC2 associated neuromuscular disease is not only categorized as HSAN, but also listed under CMT type 2 (axonal type) or HSMN type 2^12,18.

Diagnosis

Diagnosis can be made by the following: Molecular genetic test, detailed clinical evaluation and family history, Nerve Conduction Velocity(NCV)test, Electromyography(EMG), autonomic reflex test¹².  Blood test for HSAN1A biomarker deoxySLs can be done in University Hospital Zürich^6,16.

Potential HSAN1A patients often face challenges in getting the exact diagnosis.  Since its symptoms very much resemble other subtypes of CMT, ie. CMT2B that is caused by the rab7 gene, diagnosis is often based on a genetic test.  Unfortunately, genetic testing is still not commonly available in every country worldwide or affordable to everyone.  Even if a patient has access to it, if the result shows a mutation in SPTLC1 gene with unknown significance (meaning unsure if the mutation is benign or causes disease) then the blood analysis for deoxySL- the biomarker for HSAN1A would need to be involved. However, this test is not commonly or commercially available, and international shipping for bio-samples is not always easy; hence, the suspicious mutation might remain unconfirmed whether it causes the disease.

Prevalences

The occurrence of HSAN1A in general population is from 1:100,000 to 2:1,000,000^11,12

It is very difficult to predict the occurrence due to some patients’ symptoms only showing sensory nerve damage with muscle weakness or atrophy but no autonomic nerve issues and thus are diagnosed with CMT.  SPTLC1 was previously not in the C.M.T. Genetic Screening panel; therefore patients might miss this gene even if they had undergone a genetic test.

Treatment  

Currently there is no known cure. However, something worth mentioning is the serine therapy.  Since the mutated SPT enzyme not only incorporates L-serine but also L-alanine, it is thought that if the serine/alanine ratio in HSAN1 patients is increased, there might be more chance for the mutated SPT enzyme to incorporate L-serine and lessen the chance to take in L-alanine, and thus the formation of deoxySL will be reduced and hence slow the progression of the disease? 

From a genetic mouse model that carries C133W mutation in SPTLC1, researchers discovered that a 10% serine enriched diet would result in dramatic decrease of deoxySA level within just 2-4 days.  Moreover, a 10-month treatment of serine (10% serine enriched diet), the C133W mice’s mechanical sensitivity and motor performance improved compared to the untreated C133W mice.  

With such good results, a pilot human trial was conducted in 2010.  It was a short-term 10-week study with 14 HSAN1 patients who carry the C133Y mutation of SPTLC1 enrolled.  Patients were divided into 2 groups, treated with either low dose 200 mg/kg/day (200 mg of L-serine based on patient’s weight by kilogram per day) or high dose 400 mg/kg/day. The results showed that for both groups deoxySL level decreased within a month, with the high dose decreasing more than the low dose.  In this study, effects on motor or sensitivity performance were not assessed as the biological reaction was the main research focus; furthermore improvement was not expected due to the long-term neurological impairment that was unlikely to be relieved by the short term treatment period.  Nevertheless, some patients reported increase in sensation including hand tingling, and menstrual cramps and improvements in skin firmness as well as faster nail and hair growth¹³. (The side effects in the pilot study include nausea, vomiting, nystagmus, and myoclonus, but they were reversible)

In 2017, researchers completed a long term 2-year clinical trial on HSAN1A patients with oral L- Serine. (ClinicalTrial.gov identifier NCT ‪01733407) .  In total there were 18 HSAN1A patients enrolled and 16 of them completed the study.  Participants were randomly divided equally into 2 groups.  Half received serine, and half received a placebo (placebo controlled); the appearance, taste, and smell of the placebo and serine are completely identical.  Neither the testing staff nor the patients knew which study drug was being given (double blind).  For the first year, each participant of the serine group received 400mg/kg/day while the other group was provided with placebo with the same dose.  At one year, label is opened and both groups were all given serine.  The results showed that serine group experienced improvements for 2 years in a row in the area of sensory perception as well as improved strength in arms and legs measured by Charcot-Marie-Tooth Neuropathy Score version 2 while the placebo group only experienced improvements during the second year when given the serine treatment.  Moreover,  the neurotoxic lipids deoxySA was decreased 60% at one-year end point for the L-Serine group while the placebo group had increased by 9%.  When the placebo group switched over to the L-Serine treatment in the second year, their deoxySA levels decreased 66%. There were mild to moderate side effects in the study, but no serious ones. (see published paper for details).  This study showed concluded that high dose Serine therapy appears safe for HSAN1A patients and is potentially effective at slowing disease progression¹⁶. 

(Note: The number of patients who participated in this trial was very small; any HSAN1 affected individuals interested in proceeding with serine therapy, please consult with your doctor.)

Pathogenic mutation 

As of today, confirmed and published pathogenic variants in SPTLC1 gene includes: SPTLC1 p. C133W, C133Y, C133R, C133F, V144D, S331F, S331Y, A352V^1,2,7,8,19.

Inheritance 

HSAN1A is inherited in an autosomal dominant pattern.

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Reference  

¹ Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, de Jong P, Brown RH Jr. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet. 2001 Mar;27(3):261-2. doi: 10.1038/85817. PMID: 11242106. 

² Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet. 2001 Mar;27(3):309-12. doi: 10.1038/85879. PMID: 11242114.

³ Hornemann T, Penno A, Rütti MF, Ernst D, Kivrak-Pfiffner F, Rohrer L, von Eckardstein A. The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J Biol Chem. 2009 Sep 25;284(39):26322-30. doi: 10.1074/jbc.M109.023192. Epub 2009 Aug 1. PMID: 19648650; PMCID: PMC2785320.

⁴ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {605713}: {2019 Nov 4}: World Wide Web URL: https://omim.org/

⁵ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {611120}: {2010 Sept 23}:  World Wide Web URL: https://omim.org/

⁶ Penno A, Reilly MM, Houlden H, Laurá M, Rentsch K, Niederkofler V, Stoeckli ET, Nicholson G, Eichler F, Brown RH Jr, von Eckardstein A, Hornemann T. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem. 2010 Apr 9;285(15):11178-87. doi: 10.1074/jbc.M109.092973. Epub 2010 Jan 22. PMID: 20097765; PMCID: PMC2856995.

⁷ Rotthier A, Penno A, Rautenstrauss B, Auer-Grumbach M, Stettner GM, Asselbergh B, Van Hoof K, Sticht H, Lévy N, Timmerman V, Hornemann T, Janssens K. Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I. Hum Mutat. 2011 Jun;32(6):E2211-25. doi: 10.1002/humu.21481. Epub 2011 Feb 24. PMID: 21618344.

⁸ Auer-Grumbach M, Bode H, Pieber TR, Schabhüttl M, Fischer D, Seidl R, Graf E, Wieland T, Schuh R, Vacariu G, Grill F, Timmerman V, Strom TM, Hornemann T. Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype. Eur J Med Genet. 2013 May;56(5):266-9. doi: 10.1016/j.ejmg.2013.02.002. Epub 2013 Feb 27. PMID: 23454272; PMCID: PMC3682180.

⁹Alecu I, Tedeschi A, Behler N, Wunderling K, Lamberz C, Lauterbach MA, Gaebler A, Ernst D, Van Veldhoven PP, Al-Amoudi A, Latz E, Othman A, Kuerschner L, Hornemann T, Bradke F, Thiele C, Penno A. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction. J Lipid Res. 2017 Jan;58(1):42-59. doi: 10.1194/jlr.M068676. Epub 2016 Nov 23. PMID: 27881717; PMCID: PMC5234710.

¹⁰ Houlden H, King R, Blake J, Groves M, Love S, Woodward C, Hammans S, Nicoll J, Lennox G, O’Donovan DG, Gabriel C, Thomas PK, Reilly MM. Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). Brain. 2006 Feb;129(Pt 2):411-25. doi: 10.1093/brain/awh712. Epub 2005 Dec 19. PMID: 16364956.

¹¹ Reilly MM.  Hereditary sensory neuropathy type 1 [Internet].  Danbury (CT): National Organization for Rare Disorders; 1991 [updated 2017; cited 2020 Nov 1].  Available from: https://rarediseases.org/rare-diseases/hereditary-sensory-neuropathy-type-i/

¹²  Nicholson GA. Hereditary Sensory Neuropathy Type IA. 2002 Sep 23 [Updated 2015 Sep 10]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. https://www.ncbi.nlm.nih.gov/medgen/C0020071

¹³ Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest. 2011 Dec;121(12):4735-45. doi: 10.1172/JCI57549. PMID: 22045570; PMCID: PMC3225995.

¹⁴ Gantner ML, Eade K, Wallace M, Handzlik MK, Fallon R, Trombley J, Bonelli R, Giles S, Harkins-Perry S, Heeren TFC, Sauer L, Ideguchi Y, Baldini M, Scheppke L, Dorrell MI, Kitano M, Hart BJ, Cai C, Nagasaki T, Badur MG, Okada M, Woods SM, Egan C, Gillies M, Guymer R, Eichler F, Bahlo M, Fruttiger M, Allikmets R, Bernstein PS, Metallo CM, Friedlander M. Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. N Engl J Med. 2019 Oct 10;381(15):1422-1433. doi: 10.1056/NEJMoa1815111. Epub 2019 Sep 11. PMID: 31509666.

¹⁵ Suh BC, Hong YB, Nakhro K, Nam SH, Chung KW, Choi BO. Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation. Mol Med Rep. 2014 Feb;9(2):481-6. doi: 10.3892/mmr.2013.1808. Epub 2013 Nov 18. PMID: 24247255.

¹⁶ Fridman V, Suriyanarayanan S, Novak P, David W, Macklin EA, McKenna-Yasek D, Walsh K, Aziz-Bose R, Oaklander AL, Brown R, Hornemann T, Eichler F. Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. Neurology. 2019 Jan 22;92(4):e359-e370. doi: 10.1212/WNL.0000000000006811. Epub 2019 Jan 9. PMID: 30626650; PMCID: PMC6345118. 

¹⁷ Scherer SS. The debut of a rational treatment for an inherited neuropathy? J Clin Invest. 2011 Dec;121(12):4624-7. doi: 10.1172/JCI60511. PMID: 22045569; PMCID: PMC3226011.

¹⁸ https://neuromuscular.wustl.edu/time/hmsn.html

 ¹⁹ C.T. Hsiao, H. C. Chao, Y.C. Liao, K.P. Lin, B.W. Soong, Y.C. Lee, Investigation for SPTLC1 mutations in a Taiwanese cohort with hereditary neuropathies. Journal of the Neurological Science. 2017. https://doi.org/10.1016/j.jns.2017.08.3516

²⁰ Thomas, P. K., and Ochoa, J. (1993) Clinical features and differential diagnosis. in Peripheral Neuropathy, 3rd Editio (Dyck, P. J., Thomas, K. P., Griffin, J. W., Low, P. A., and Poduslo, J. F. eds), pp. 749–774, Saunders Philladelphia